Submissions for variant NM_000090.4(COL3A1):c.1424C>T (p.Ala475Val)

gnomAD frequency: 0.00004  dbSNP: rs770168441

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001678587	SCV000233326	uncertain significance	not provided	2021-08-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (Stenson et al., 2014); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#199695; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918)
Ambry Genetics	RCV000248331	SCV000317731	uncertain significance	Cardiovascular phenotype	2016-05-19	criteria provided, single submitter	clinical testing	The p.A475V variant (also known as c.1424C>T), located in coding exon 20 of the COL3A1 gene, results from a C to T substitution at nucleotide position 1424. The alanine at codon 475 is replaced by valine, an amino acid with similar properties. Based on data fromExAC, the Tallele was reported in 1 of121334(<0.1%) total alleles.This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170890	SCV001333515	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-10-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170890	SCV001357971	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 475 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 1/251254 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002500524	SCV002814189	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-10-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515303	SCV003278925	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 475 of the COL3A1 protein (p.Ala475Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 199695). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV002515303	SCV004832390	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 475 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251254 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.